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Copyright of Climacteric is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This document is a reply to comments made on a previous article about the use of fezolinetant for treating vasomotor symptoms associated with menopause. The US Food and Drug Administration (FDA) investigated the potential increased risk of neoplasms (abnormal growth of tissue) with fezolinetant and found that while there was an apparent dose-response for malignancy, there were no consistent patterns related to drug exposure duration, body system, or cancer type. The authors of the reply acknowledge the increased incidence of neoplasms in patients treated with fezolinetant, but they argue that comparing the data between the fezolinetant and placebo groups with unequal follow-up durations may lead to skewed conclusions. They recommend additional long-term safety studies and close monitoring of patients using fezolinetant to make better-informed decisions about managing menopause symptoms. [Extracted from the article]

Background: The management of antidiabetic therapy in people with type 2 diabetes (T2D) has evolved beyond glycemic control. In this context, Brazil and Portugal defined a joint panel of four leading diabetes societies to update the guideline published in 2020. Methods: The panelists searched MEDLINE (via PubMed) for the best evidence from clinical studies on treating T2D and its cardiorenal complications. The panel searched for evidence on antidiabetic therapy in people with T2D without cardiorenal disease and in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or diabetic kidney disease (DKD). The degree of recommendation and the level of evidence were determined using predefined criteria. Results and conclusions: All people with T2D need to have their cardiovascular (CV) risk status stratified and HbA1c, BMI, and eGFR assessed before defining therapy. An HbA1c target of less than 7% is adequate for most adults, and a more flexible target (up to 8%) should be considered in frail older people. Non-pharmacological approaches are recommended during all phases of treatment. In treatment naïve T2D individuals without cardiorenal complications, metformin is the agent of choice when HbA1c is 7.5% or below. When HbA1c is above 7.5% to 9%, starting with dual therapy is recommended, and triple therapy may be considered. When HbA1c is above 9%, starting with dual therapyt is recommended, and triple therapy should be considered. Antidiabetic drugs with proven CV benefit (AD1) are recommended to reduce CV events if the patient is at high or very high CV risk, and antidiabetic agents with proven efficacy in weight reduction should be considered when obesity is present. If HbA1c remains above target, intensification is recommended with triple, quadruple therapy, or even insulin-based therapy. In people with T2D and established ASCVD, AD1 agents (SGLT2 inhibitors or GLP-1 RA with proven CV benefit) are initially recommended to reduce CV outcomes, and metformin or a second AD1 may be necessary to improve glycemic control if HbA1c is above the target. In T2D with HF, SGLT2 inhibitors are recommended to reduce HF hospitalizations and mortality and to improve HbA1c. In patients with DKD, SGLT2 inhibitors in combination with metformin are recommended when eGFR is above 30 mL/min/1.73 m2. SGLT2 inhibitors can be continued until end-stage kidney disease. [ABSTRACT FROM AUTHOR]

Summary: Despite being approved for clinical use, evidence of cardiovascular safety (CV) is lacking for treatment with bupropion, naltrexone, or their combination (B‐N). The purpose of the study is to determine the relationship between these treatments and the risk of major cardiovascular adverse events (MACE). Phase 3 randomized clinical trials (RCT) evaluating bupropion, naltrexone, or B‐N versus control with reported incidence of MACE. The meta‐analysis included 12 RCTs, 69% for weight loss and 29% for smoking cessation, with 19,176 patients and 7354 patient‐years who were randomized to an active treatment (bupropion [n = 2965] or B‐N [n = 6980] or naltrexone [n = 249]) versus control (placebo [n = 6968] or nicotine patch [n = 2014]). The mean age was 54 ± 8 years (55% female), and the baseline BMI was 32 ± 5 kg/m2. The additive network meta‐analysis model for random effects showed no association between bupropion, B‐N, or naltrexone and MACE (odds ratio [OR] = 0.90 [95%CI 0.65–1.25], p = 0.52; OR = 0.97 [95%CI 0.75–1.24], p = 0.79; OR = 1.08 [95%CI 0.71–1.63], p = 0.73, respectively; I2 = 0%, p = 0.86). Meta‐regression analyses showed no significant association between MACE and potential confounders from RCT demographic disparities (p = 0.58). The statistical power (post hoc two‐tailed) for non‐inferiority was 91%, giving a strong probability of validity. Naltrexone, bupropion, or B‐N is not associated with the incidence of MACE as compared with placebo. [ABSTRACT FROM AUTHOR]

Background: In current management of type 2 diabetes (T2DM), cardiovascular and renal prevention have become important targets to be achieved. In this context, a joint panel of four endocrinology societies from Brazil and Portugal was established to develop an evidence-based guideline for treatment of hyperglycemia in T2DM. Methods: MEDLINE (via PubMed) was searched for randomized clinical trials, meta-analyses, and observational studies related to diabetes treatment. When there was insufficient high-quality evidence, expert opinion was sought. Updated positions on treatment of T2DM patients with heart failure (HF), atherosclerotic CV disease (ASCVD), chronic kidney disease (CKD), and patients with no vascular complications were developed. The degree of recommendation and the level of evidence were determined using predefined criteria. Results and conclusions: In non-pregnant adults, the recommended HbA1c target is below 7%. Higher levels are recommended in frail older adults and patients at higher risk of hypoglycemia. Lifestyle modification is recommended at all phases of treatment. Metformin is the first choice when HbA1c is 6.5–7.5%. When HbA1c is 7.5–9.0%, dual therapy with metformin plus an SGLT2i and/or GLP-1RA (first-line antidiabetic agents, AD1) is recommended due to cardiovascular and renal benefits. If an AD1 is unaffordable, other antidiabetic drugs (AD) may be used. Triple or quadruple therapy should be considered when HbA1c remains above target. In patients with clinical or subclinical atherosclerosis, the combination of one AD1 plus metformin is the recommended first-line therapy to reduce cardiovascular events and improve blood glucose control. In stable heart failure with low ejection fraction (< 40%) and glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2, metformin plus an SGLT-2i is recommended to reduce cardiovascular mortality and heart failure hospitalizations and improve blood glucose control. In patients with diabetes-associated chronic kidney disease (CKD) (eGFR 30–60 mL/min/1.73 m2 or eGFR 30–90 mL/min/1.73 m2 with albuminuria > 30 mg/g), the combination of metformin and an SGLT2i is recommended to attenuate loss of renal function, reduce albuminuria and improve blood glucose control. In patients with severe renal failure, insulin-based therapy is recommended to improve blood glucose control. Alternatively, GLP-1RA, DPP4i, gliclazide MR and pioglitazone may be considered to reduce albuminuria. In conclusion, the current evidence supports individualizing anti-hyperglycemic treatment for T2DM. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of obesity has grown exponentially over the last several decades. Research has linked male obesity to changes in the gonadal axis, which can induce functional hypogonadism. Bariatric surgery provides sustained weight loss and metabolic improvement. This was a retrospective cohort study to evaluate the male gonadal axis and metabolic profiles of obese individuals during the bariatric pre- and post-operative periods while comparing them to a normal body mass index (BMI) group. Methods: Twenty-nine obese men, who underwent bariatric surgery between 2012 and 2016 at the Federal University of Santa Catarina Hospital and a control group (CG) of 29 age-matched men with normal BMI, were analyzed. Bariatric pre- and 6-month post-operative data were compared with the CG. Results: The study group (G1) presented an average age, weight, and BMI of 42.8 ± 9.5 years, 155.2 ± 25.8 kg, and 50.6 ± 7.1 kg/m2, respectively. The pre-operative total testosterone (TT) G1 values were different from the CG (229.5 ± 96.4 versus 461.5 ± 170.8 ng/dL, p < 0.01). Bariatric surgery promoted a statistically significant improvement in weight, TT, and metabolic profiles in surgical patients. Conclusion: Functional hypogonadism is prevalent in obese men, and we must be aware of this diagnosis. Although studies defining the best diagnostic parameters and indication of adequate hormone replacement therapy are lacking, an increase in TT levels during the first 6 months after bariatric surgery was identified in our study. Previous studies have shown that gonadal function can normalize after metabolic improvement. [ABSTRACT FROM AUTHOR]

Chronic metabolic alterations may represent a risk factor for the development of cognitive impairment, dementia, or neurodegenerative diseases. Hyperglycemia and obesity are known to imprint epigenetic markers that compromise the proper expression of cell survival genes. Here, we showed that chronic hyperglycemia (60 days) induced by a single intraperitoneal injection of streptozotocin compromised cognition by reducing hippocampal ERK signaling and by inducing neurotoxicity in rats. The mechanisms appear to be linked to reduced active DNA demethylation and diminished expression of the neuroprotective transcription factor REST. The impact of the relationship between adiposity and DNA hypermethylation on REST expression was also demonstrated in peripheral blood mononuclear cells in obese children with reduced levels of blood ascorbate. The reversible nature of epigenetic modifications and the cognitive impairment reported in obese children, adolescents, and adults suggest that the correction of the anthropometry and the peripheral metabolic alterations would protect brain homeostasis and reduce the risk of developing neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a worldwide core public health problem affecting mostly young male subjects. An alarming increase in incidence has turned TBI into a leading cause of morbidity and mortality in young adults as well as a tremendous resource burden on the health and welfare sector. Hormone dysfunction is highly prevalent during the acute phase of severe TBI. In particular, investigation of the luteinizing hormone (LH) and testosterone levels during the acute phase of severe TBI in male has identified a high incidence of low testosterone levels in male patients (36.5-100%) but the prognostic significance of which remains controversial. Two independent studies showed that normal or elevated levels of LH levels earlier during hospitalization are significantly associated with higher mortality/morbidity. The association between LH levels and prognosis was independent of other predictive variables such as neuroimaging, admission Glasgow coma scale, and pupillary reaction. The possible mechanisms underlying this association and further research directions in this field are discussed. Overall, current data suggest that LH levels during the acute phase of TBI might contribute to accurate prognostication and further prospective multicentric studies are required to develop more sophisticated predictive models incorporating biomarkers such as LH in the quest for accurate outcome prediction following TBI. Moreover, the potential therapeutic benefits of modulating LH during the acute phase of TBI warrant investigation. [ABSTRACT FROM AUTHOR]

Background: Since the first position statement on diabetes and cardiovascular prevention published in 2014 by the Brazilian Diabetes Society, the current view on primary and secondary prevention in diabetes has evolved as a result of new approaches on cardiovascular risk stratification, new cholesterol lowering drugs, and new anti-hyperglycemic drugs. Importantly, a pattern of risk heterogeneity has emerged, showing that not all diabetic patients are at high or very high risk. In fact, most younger patients who have no overt cardiovascular risk factors may be more adequately classified as being at intermediate or even low cardiovascular risk. Thus, there is a need for cardiovascular risk stratification in patients with diabetes. The present panel reviews the best current evidence and proposes a practical riskbased approach on treatment for patients with diabetes. Main body: The Brazilian Diabetes Society, the Brazilian Society of Cardiology, and the Brazilian Endocrinology and Metabolism Society gathered to form an expert panel including 28 cardiologists and endocrinologists to review the best available evidence and to draft up-to-date an evidence-based guideline with practical recommendations for risk stratification and prevention of cardiovascular disease in diabetes. The guideline includes 59 recommendations covering: (1) the impact of new anti-hyperglycemic drugs and new lipid lowering drugs on cardiovascular risk; (2) a guide to statin use, including new definitions of LDL-cholesterol and in non-HDL-cholesterol targets; (3) evaluation of silent myocardial ischemia and subclinical atherosclerosis in patients with diabetes; (4) hypertension treatment; and (5) the use of antiplatelet therapy. Conclusions: Diabetes is a heterogeneous disease. Although cardiovascular risk is increased in most patients, those without risk factors or evidence of sub-clinical atherosclerosis are at a lower risk. Optimal management must rely on an approach that will cover both cardiovascular disease prevention in individuals in the highest risk as well as protection from overtreatment in those at lower risk. Thus, cardiovascular prevention strategies should be individualized according to cardiovascular risk while intensification of treatment should focus on those at higher risk. [ABSTRACT FROM AUTHOR]

Mitochondrial respiratory chain complexes enzymatic (MRCCE) activities were successfully evaluated in frozen brain samples. Epilepsy surgery offers an ethical opportunity to study human brain tissue surgically removed to treat drug resistant epilepsies. Epilepsy surgeries are done with hemodynamic and laboratory parameters to maintain physiology, but there are no studies analyzing the association among these parameters and MRCCE activities in the human brain tissue. We determined the intra-operative parameters independently associated with MRCCE activities in middle temporal neocortex (Cx), amygdala (AMY) and head of hippocampus (HIP) samples of patients (n = 23) who underwent temporal lobectomy using multiple linear regressions. MRCCE activities in Cx, AMY and HIP are differentially associated to trans-operative mean arterial blood pressure, O saturation, hemoglobin, and anesthesia duration to time of tissue sampling. The time-course between the last seizure occurrence and tissue sampling as well as the sample storage to biochemical assessments were also associated with enzyme activities. Linear regression models including these variables explain 13-17 % of MRCCE activities and show a moderate to strong effect (r = 0.37-0.82). Intraoperative hemodynamic and laboratory parameters as well as the time from last seizure to tissue sampling and storage time are associated with MRCCE activities in human samples from the Cx, AMYG and HIP. Careful control of these parameters is required to minimize confounding biases in studies using human brain samples collected from elective neurosurgery. [ABSTRACT FROM AUTHOR]

Copyright of Clinical & Biomedical Research is the property of Clinical & Biomedical Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Changes in hormone blood levels during the acute phase of traumatic brain injury (TBI) have been described in the literature. The objective was to investigate the association among several hormones plasma levels in the acute phase of severe TBI and the hospital mortality rate of male patients. Methods: The independent association among plasma levels of TSH, LH, FSH, GH, free T4, cortisol, IGF-1 and total testosterone was measured 10 hours and 30 hours after severe TBI and the hospital mortality of 60 consecutive male patients was evaluated. Results: At least one hormonal level abnormality was demonstrated in 3.6-73.1% of patients. The multiple logistic regressions showed a trend for an independent association among hospital mortality and normal or elevated LH levels measured at 10 hours (OR = 3.7, 95% CI = 0.8-16.3, p = 0.08) and 30 hours (OR = 3.9, 95% CI = 0.9-16.7, p = 0.06). Admission with abnormal pupils and a lower Glasgow Coma Score also were independently associated with hospital mortality. Conclusion: The hormonal changes are frequent in the acute phase of severe TBI. The hormones plasma levels, excepting the LH, are not highly consistent with the hospital mortality of male patients. [ABSTRACT FROM AUTHOR]

Objectives Traumatic brain injury ( TBI) is a main cause of mortality and morbidity. Association studies between hospitalization variables and cognitive impairment after TBI are frequently retrospective, including non-consecutive patients showing variable degrees of TBI severity, and poor management of missing (drop out) cases. Methods We assessed prospectively the demographic and hospitalization variables of 234 consecutive patients with severe TBI (admission Glasgow Coma Scale [ GCS] ≤8) and determined their independent association with cognitive performance in a representative sample ( n = 46) of surviving patients ( n = 172) evaluated 3 (±1.8) years after hospitalization. Results In all, 85% of patients were male and the mean age was 34 ( SD ±13) years. The education level was 9 (±4.7) years. As expected, education and age showed a moderately to strong linear relationship with the cognitive performance in 14 of 15 neuropsychological tests ( R coefficient = 0.6-0.8). The cognitive test scores were not independently associated with gender, admission GCS, associated trauma, and Marshal CT classification. Admission-elevated blood glucose levels and the presence of sub-arachnoid haemorrhage were independently associated with lower scores on Rey Auditory Verbal Learning retention and Logical Memory-I tests, respectively. Conclusions After correction for education and age distribution, the variables that are commonly associated with mortality or Glasgow Outcome Scale including admission pupils' examination, Marshal CT Classification, GCS, and serum glucose showed a limited predictive power for long-term cognitive prognosis. Identification of clinical, radiological, and laboratory variables as well as new biomarkers independently associated with cognitive outcome remains an important challenge for further work involving severe TBI patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) has a high prevalence and incidence around the world. The complex pathophysiology mechanism is among the barriers for diabetes treatment. Type 2 diabetes patients have dysfunction in incretin hormones (as glucagon-like peptide-1 or GLP-1, and glucose-dependent insulinotropic polypeptide or GIP). By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, it is possible to slow the inactivation of GLP-1 and GIP, promoting blood glucose level reduction in a glucose-dependent manner. Linagliptin is a highly specific and potent inhibitor of DPP-4 that is currently indicated for the treatment of type 2 diabetes. Clinical studies with linagliptin demonstrated efficacy in reducing glycated hemoglobin (HbA1c) levels in type 2 diabetes patients, while maintaining a placebo-like safety and tolerability profile. Linagliptin has an interesting pharmacokinetic profile in terms of its predominantly non-renal elimination and the main implication of this characteristic is that no dose adjustment is necessary in patients with renal disease. Also, no dose adjustment is required in patients with hepatic insufficiency, as well in elderly or obese patients. This article will review the pharmacokinetic profile, efficacy data and safety aspects of linagliptin in type 2 diabetes patients. [ABSTRACT FROM AUTHOR]

Background: Cytokines have been shown to be involved in traumatic brain injury (TBI). We investigated the independent association between serum levels of IL-10 and TNF-α and hospital mortality of patients with severe TBI. Methods: Serum IL-10 and TNF-α levels were determined after a median period (interquartile range (IQ) 25-75) of 10 h (IQ 5-18) after severe TBI in 93 consecutive patients and in randomly selected patients with mild (n = 18) and moderate (n = 16) TBI. In patients with severe TBI, additional blood samples were analyzed 30 h (IQ 22-37) and 68 h (IQ 55-78) after TBI. Age, gender, computed tomography findings, Glasgow Coma Scale score (GCS) and pupil reactions at admission, associated trauma and hospital mortality were collected. Results: Elevated serum levels of IL-10, but not TNF-α, correlated significantly with GCS severity (R2 coefficient, p < 0.0001) and were found to be associated with hospital mortality in patients with severe TBI. Elevated IL-10 remained associated with mortality (p = 0.01) in a subset of patients with isolated severe TBI (n = 74). Multiple logistic regression analysis showed that higher IL-10 levels (>90 pg/ml) at 10 or 30 h after TBI were 6 times (odds ratio (OR) 6.2, 95% confidence interval (CI) 1.2-25.1, p = 0.03) and 5 times (OR 5.4, 95% CI 1.2-25.1, p = 0.03), respectively, more frequently associated with hospital mortality than lower levels (<50 pg/ml), independently of age, GCS as well as pupil reactions at admission and associated trauma. Conclusions: Serum IL-10 levels may be a useful marker for severe TBI prognosis. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]